Histamine is important in human physiology because it is one of the chemicals released from certain cells (particularly mast cells) upon tissue injury or during the neutralisation of foreign material (e.g. antigens) by certain types of antibodies. Released histamine tends to dilate blood capillaries, often causing the skin to appear red and feel warm, and makes the capillaries more permeable, allowing fluid to escape into the surrounding tissue.
The biological activity of histamine is closely related with allergic responses and its deleterious effects, such as inflammation. Events that induce the inflammatory response include physical stimulation (including trauma), chemical stimulation, infection, and invasion by microorganisms. The inflammatory response is characterised by pain, increased temperature, redness, swelling, reduced function, itch, or any combination of these.
Mast cell degranulation (exocytosis) releases histamine and leads to an inflammatory response. A wide variety of immunological stimuli and non-immunological stimuli may cause the activation, recruitment and degranulation of mast cells. The activation of mast cells initiates allergic inflammatory responses, which in turn cause the recruitment of other effector cells that further contribute to the inflammatory response.
The numerous functions that are exerted by histamine are mediated through at least four pharmacologically distinct receptors, which are all members of the G-protein-coupled receptor family. The H1 receptor is expressed in the brain, endothelial cells, and smooth muscle cells. Many of its functions contribute to allergic responses, and H1 receptor antagonists have been very successful drugs for the treatment of allergies. The H2 receptor has been demonstrated to function as a key modulator for gastric acid secretion, and H2 receptor antagonists are widely used for the treatment of gastrointestinal ulcers. The H3 receptor is predominantly expressed in the human central nervous system. It is believed to function as a presynaptic release-controlling receptor that may regulate histamine, norepinephrine, serotonin, GABA, acetylcholine, and other neurotransmitters. The histamine receptors couple to different signalling pathways via different G-proteins.
Recently, several groups have identified and characterised a fourth histamine receptor (see, e.g., T. Oda et al., J. Biol. Chem. 2000, 275 (47), 36781-36786; C. Liu et al., Mol. Pharmacol. 2001, 59 (3), 420-426; T. Nguyen et al., Mol. Pharmacol. 2001, 59 (3), 427-433; Y. Zhu et al., Mol. Pharmacol. 2001, 59 (3), 434-441; K. L. Morse et al., J. Pharmacol. Exp. Ther. 2001, 296 (3), 1058-1066). The histamine H4 receptor is a seven-transmembrane, G-protein-coupled receptor with approximately 40% homology to the histamine H3 receptor. However, in contrast to the H3 receptor, the H4 receptor is expressed at greater levels in e.g. mast cells, eosinophils and a variety of other cells of the immune system.
It has been shown that administration of a histamine H4 receptor antagonist inhibits histamine H4 receptor-mediated calcium influx and chemotaxis of mast cells (Thurmond et al., J. Pharmacol. Exp. Ther. 2004, 309 (1), 404-413) and eosinophils (Raible et al., Am. J. Respir. Crit. Care Med. 1994, 149 (6), 1506-1511). This suggests an important role for the histamine H4 receptor for the treatment of inflammatory diseases such as asthma, inflammatory bowel disease and several dermatological disorders. Further, histamine H4 is associated with cancer and itch. See J. K. Bell et al., Br. J. Pharmacol. 2004, 142 (2), 374-380; and F. Cianchi et al., Clin. Cancer Res. 2005, 11, 6807-6815.
US2005/0070527 describes 1H-quinoxaline compounds that inhibit leukocyte recruitment and modulate the H4 receptor, and their use in treating conditions such as inflammation.
Further prior art in this general area includes WO2006/050965, WO02/072548, US20050070550A1, WO2007/031529, WO2004/022537, EP1767537A1 and US2006/0111416.
PCT/EP2007/056689 discloses compounds of formula I
wherein
Q is CR1 or N;
X is CR2 or N, provided that Q and X are not both N;
Y is CR3 or N;
Z is CH or N;
R1, R2, R3, R4, R5 and R6 are independently H, F, Cl, Br, I, or a hydrocarbon group which optionally contains one or more heteroatoms; and
R7 is a heterocyclic group including one or more N atoms;
or a pharmaceutically acceptable salt, ester or solvate thereof.